The Course and Outcome of Bipolar Disorders in Youth (COBY) study has comprehensively characterized the clinical course of a large sample of youth with bipolar disorder (BD), and has identified demographic and clinical factors that are associated with different illness courses. To date, however, COBY has not included neuroimaging assessments. Including such assessments now will allow, for the first time, an evaluation of the impact of 13-year course of BD and treatment upon neural circuitry function and structure. Furthermore, the majority of COBY participants are currently between 18-30 years old, when the brain, and prefrontal cortex in particular, continues to develop. Including neuroimaging assessments in COBY participants now can thus take advantage of the neurodevelopmental processes occurring between 18-30 years where there are unique opportunities to intervene therapeutically to help normalize abnormalities in neural functioning and structure. Focusing on this age range will also provide a critically important opportunity to determine the extent to which neuroimaging measures predict future clinical course in adulthood. Having normal prefrontal cortical function and structure may predict better clinical course in adulthood, even in COBY participants with poor clinical course in youth, and may lead to decisions to reduce, or even stop, specific treatments in these individuals. In the proposed study, we will determine how previous BD clinical course (e.g., % time with mood symptoms vs. euthymic; % time with comorbid disorders) and treatment exposure from childhood into adulthood impacts neural circuitry functioning and structure supporting key NIMH RDoC information processing domains, and compare neuroimaging findings in COBY participants with those of demographically-matched healthy controls (Aim 1). We will also determine whether neuroimaging measures predict illness course in adulthood, beyond demographic and clinical factors, and previous clinical course in youth (Aim 2). We will use machine learning to explore patterns of wholebrain functioning, white and gray matter structure, and clinical and demographic measures, that most accurately predict future clinical course at the individual subject level. The proposed study also provides a valuable opportunity to inform the field regarding the clinical and functional course and outcome from youth into adulthood in a large, well-characterized sample of people with BD. This is important because the clinical outcome of BD youth in adulthood remains uncertain, as only two studies with a total of 72 subjects followed BD youth into their early twenties. Structural and functional neuroimaging techniques will be employed in a representative subsample of COBY participants (n=120), and healthy controls (n=50). Comprehensive assessments of psychopathology and functioning will be collected at the time of neuroimaging, and twice more during the proposed project period in the 120 COBY participants. This proposal accords with the NIMH's mission to define developmental trajectories of mental disorders and develop strategies to better define risk and protective factors for disease trajectories across the lifespan, and with the RDoC initiative.